1. Field of the Invention
The present invention relates to liposome preparations and more particularly, to liposome preparations comprising cholesterol derivatives having a negative charge as a liposome membrane constituent, in which Adriamycin is entrappped. The preparations are utilized in the medical field.
2. Statement of the Prior Art
Adriamycin has been widely used as an anti-tumor agent. Due to its positive charge in physiological pH region, however, Adriamycin encounters problems that Adriamycin binds to membrane constituents such as cells, mitochondria, etc., especially to phospholipids negatively charged, thus leading to accumulative cardiotoxicity as a cause therefor. Accordingly, its dosage is limited. In addition, Adriamycin has a high affinity to vital tissues so that even when it is intravenously administered, Adriamycin rapidly disappears out of blood.
In order to solve the foregoing problems, there are provided Adriamycin-entrapped liposome preparations in which acidic glycolipids such as Sulfatides having a negative charge in a physiological pH region, or glycolipids having a sulfo group, especially Sulfatides (Japanese Patent Application Laid-Open Nos. 62-129221 and 63-112512).
On the other hand, in Adriamycin-entrapped liposome preparations, it is known to use sterols having a negative charge such as cholesterol sulfate and cholesterol hemisuccinate as the liposome membrane constituent (International Patent Application No. PCT/US88/01573 : International Publication No. W088/09168).
The aforesaid liposome preparations obtained by incorporating Sulfatide into the liposome membrane constituent exhibit effects that they have a high content of Adriamycin to keep a high blood level of Adriamycin over a long period of time and less accumulate Adriamycin on the heart, as compared to the case where Adriamycin is administered in an aqueous solution and therefore, cardiotoxicity can be reduced.
However, it has not yet been established to chemically synthesize Sulfatides, but they are obtained by extracting and purifying from animal, e.g., bovine brain.
For this reason, it is difficult to obtain pure compounds. In addition, extraction and purification take much time. In the case of utilizing commercially available compounds, costs are extremely high. Thus, there was a problem that liposome preparations containing these components as liposome membrane constituents could not be produced in large quantities from an industrial viewpoint.
As a result of extensive investigations on liposome membrane constituents which can be easily synthesized at low costs, the present inventors have found that cholesterol derivatives having a negative charge and represented by general formula: EQU R--CO--A.sub.1
(wherein R represents a cholesterol residue, and A.sub.1 represents an amino acid residue), and represented by general formula: EQU R--A.sub.2
(wherein R represents a cholesterol residue, and A.sub.2 represents a fatty acid residue), had effects equivalent to Sulfatide.
That is, it has been found that Adriamycin-entrapped liposome preparations comprising these cholesterol derivatives having a negative charge as liposome membrane constituents have a high content of Adriamycin and when administered in a living body, can maintain high blood level of Adriamycin over a long period of time, reduce distribution of Adriamycin on the heart and reduce systemic toxicity. The present invention has thus been completed.